Almutairi, 2018;2(1):9–15. International Journal of Medicine in Developing Countries https://doi.org/10.24911/IJMDC.2.1.3

REVIEW ARTICLE in children Rawan Ali Almutairi1*

ABSTRACT Physicians consider the short stature as one of the most common causes of referral to pediatric clinics. The initial evaluation of short stature should include a history, a physical examination, an accurate assess- ment of growth, calculation of the growth velocity and mid-parental height, and radiography to evaluate bone age. The recommendations for short stature management differ according to the level of (GH), wherein the case of GH deficiency; the patient may receive markedly different recommendations. Keywords: Short stature, growth hormone, growth velocity, SHOX, .

Introduction about the English published articles only, which were published from 1995 to 2017. There is a large number of children who are referred to pediatric endocrinology clinics [1]. Short stature is an Epidemiology adult height that is more than 2 standard deviations (SD) under the mean for age and gender; also, it corresponds The prevention of short stature and its complications to the shortest 2.3% of individuals [2]. In developed require firstly, good knowledge of its prevalence [4], so countries, this typically includes adult men who are in our literature, we will review some previous studies shorter than 166 cm (5 ft 5 in) tall and adult women who in different countries. A study conducted by El Mouzan are shorter than 153 cm (5 ft 0 in) tall. By comparison, et al. [9] in Saudi Arabia reported that the overall the median or typical adult height in these populations prevalence of moderate short stature was 11.3% in boys (as the widely abundant statistics from these countries and 10.5% in girls, while the prevalence of severe short clearly state) is about 177 cm (5 ft 10 in) for men and stature was 1.8% in boys and 1.2% in girls. By using 164 cm (5 ft 5 in) for women [3]. Perception of the the 1978 World Health Organization (WHO), the 2000 prevalence of short stature is the first important step for Centers for Control, and the 2007 WHO growth prevention of this condition and its complications [4]. In references, the prevalence of moderate short stature was the United States, 2.2 million children less than 18 years 12.1%, 11%, and 11.3% in boys and 10.9%, 11.3%, and of age have heights below the third percentile [5]. In 10.5% in girls, respectively. the case of diagnosis of short stature in children in their Another study which conducted in West Bank, Palestine first or second year the case is familial (genetic) short by Mikki et al. [10] stated that by studying the prevalence stature and delayed growth, which are non-pathologic of stunting in school children aged 13–15 years in variants of growth [6]. The recommendations for short Ramallah, it was found that 9.2% of boys and 7.3% of stature management differ according to the level of girls were suffering from stunting; and in Hebron, 9.4% growth hormone (GH). In GH deficiency, short stature and 4.2%, in boys and girls, respectively. is managed by the supplementation of GH. Recombinant Haboubi et al. [11] conducted a study of a comparison DNA-derived human GH has been available since 1985, between adolescents aged 11–16 living in South India for more than 50 years; [7]. Different recommendations and a sample from the same ethnic background but which vary in complexity and costs were advised to living in Dubai, United Arab Emirates (UAE), using children with short stature that is not related to GH the 1978 NCHS/WHO reference, they reported that deficiency [8]. Material and Methods Correspondence to: Rawan Ali Almutairi We used scientific websites such as PubMed, Google *King Khalid University Hospital, King Saud University, Scholar, and ResearchGate to get related articles about Riyadh, Saudi Arabia. this subject. The research process involved specific Email: [email protected] keywords “short stature, growth hormone, growth Full list of author information is available at the end of velocity, SHOX, and idiopathic short stature” to find the article. more articles on the subject. We were more concerned Received: 9 November 2017 | Accepted: 25 December 2017

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the prevalence of short stature among children who are in distinguishing children with short familial stature from living in India was 38.8% and 36.9% in boys and girls, those with constitutional delay of growth [6]. respectively, compared to 8.9% and 11.6% in boys and girls, respectively, for South Indian students living in Idiopathic short stature (ISS) the UAE. When the height is below 2 SD of the mean for age, In China, a cross-sectional study reported that the in the absence of any endocrine, metabolic or another prevalence of stunting in the age group 10–18 years was diagnosis, the case was diagnosed as ISS. ISS children 23% in 1991, which decreased to 19% in 1993 [12]. The were characterized by having normal growth velocity, prevalence of stunting (defined as height for age z score biochemical tests or another evidence for a specific < −2 SD) in a rural region of South Africa was between growth retarding condition, which give normal results 5% and 7% in children and adolescents aged 5–20 years, for endocrine screening tests including those for GH when the 1978 NCHS/WHO reference was used [13]. deficiency. Genome-wide studies indicate that several Similar prevalence levels of 5.7% were reported from hundred genetic variations explain the majority of Turkey in school children between 6–16 years of age [14]. the variation in adult height, each with a small effect A Pakistani study stated that the prevalence of short [17,18]. In a minor population, short stature is caused by stature was 16.5% among children who are aged from 6 specific genetic variations with huge effect. For example, to12 years [15]. emerging evidence suggests that 1%–4% of individuals who would otherwise have been classified as having Classification and Causes “idiopathic” short stature were caused by mutations in the short stature homeobox (SHOX) gene [6]. Standard variants of growth; Familial short stature Pathologic Causes of Growth Failure The most often normal variant of short stature is termed familial or genetic short stature (Figure 1). These Systemic disorders with secondary effects on growth individuals were usually characterized by having lower than normal growth velocity throughout life and their Almost any severe disease can be considered as the bone size remains constant even with growth, this helped second cause of growth failure. The abnormalities of

Figure 1. Growth curve in a male with short familial stature. The growth velocity is normal from 5 years of age onwards, with the height being below, but parallel to, the third percentile [16].

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growth and development were undoubtedly noticed and increased caloric utilization. After diagnosis, the in children with acute or chronic illnesses because of chemotherapy and radiotherapy side effects including increased energy needs or nutrition (e.g., decreased intake , nausea, and vomiting also can lead to abnormal or malabsorption). The normal growth rate is affected by growth. These symptoms often decreased within 1–2 radiation therapy, glucocorticoids and stimulants used years of treatment, and some children then have normal for attention deficit disorder or chemotherapy (mostly growth [25]. transient and it may have a small lasting impact if treatment is prolonged) [19]. Pulmonary Disease Under-Nutrition Cystic fibrosis is a pulmonary and gastrointestinal disease. Growth failure in this disorder may be caused by can lead to the short stature which is multiple mechanisms, including inadequate food intake, characterized by a delayed pattern of growth. Under- chronic infection, maldigestion or malabsorption, and nutrition can be isolated (e.g., caused by an inadequate increased energy requirements (work of breathing) [26]. food supply or a self-imposed restriction, such as fear of obesity) [20]. Cardiac Disease Glucocorticoid Therapy A defect in the growth is common in children who are suffering from heart disease of any cause. The major Glucocorticoids is one of the most important causes, pathogenetic factors are a loss of appetite and increased which leads to short stature in children, inspite of they basal energy requirements [27]. are used for the treatment in a variety of . The growth failure resulting as a result of excess consumption Immunologic Disease of glucocorticoids may be asymptomatic and it is known as Cushing’s syndrome. The glucocorticoids cause Human immunodeficiency virus infection is related the short stature by interfering with the pathways of to growth retardation. Mechanisms include anorexia, endogenous GH secretion and action, bone formation, malabsorption, diarrhea, severe infections, and failure of nitrogen retention, and collagen formation [21]. one or more organ systems [28]. Gastrointestinal Disease Metabolic Diseases

The failure of growth which results from gastrointestinal Growth failure is common in kids and young people disease is characterized by a more significant deficit in with a lot of considerable inherent issue of metabolism. weight than the height (i.e., they are -for- Among obtained metabolic illnesses, the most widely height) in contrast to those with endocrine disorders, recognized are Type 1 diabetes mellitus. In the past, Type who are often overweight-for-height [6]. The Crohn 1 diabetes mellitus was a vital reason for short stature disease is a gastrointestinal disease in which about 50% and lessened growth due to caloric deficiency resulting of children who suffer from it have a decrease in height from severe glucosuria [29]. However, it is presently velocity before the onset of gastrointestinal symptoms, uncommon in the light of enhancements in the treatment. and about 10% have short stature when the Crohn Children with Type 1 diabetes have low IGF-1 generation disease is diagnosed [22]. The growth failure is closely or activity, and there is a negative relationship between related to the inflammatory disease process (mediated by hemoglobin A1C (as a file of metabolic control) and proinflammatory cytokines) as well as decreased food grown-up stature [30]. intake, malabsorption and high-dose glucocorticoids if Endocrine Causes Growth Failure used for treatment. Similarly, celiac disease can present with growth failure, especially in younger children [23]. The essential endocrine issues with consequences for Rheumatologic Disease growth are uncommon; however, they are necessary to recognize because they can be dealt with. All in all, Rheumatologic diseases in children, especially systemic these disorders are described by extreme weight for juvenile idiopathic arthritis (JIA), are frequently stature. They ought to be considered in any kid with associated with growth retardation [24]. The growth extraordinarily decreased height velocity, and particularly retardation in rheumatologic disorders may be caused in those with other pituitary issue, cerebrum tumors, by the proinflammatory cytokines and is also caused septo-optic dysplasia (otherwise called optic nerve by excessive use of glucocorticoids [24]. Common hypoplasia), midline mind and facial deformities, neonatal presenting symptoms of JIA are fever, arthralgias, rash, hypoglycemia, history of cranial light, or a familial and lymphadenopathy, in addition to growth failure [6]. example of development hormone inadequacy [31]. Cancer Cushing’s Syndrome

Cancer may affect the children growth before diagnosis Cushing’s disorder is caused by extreme glucocorticoids because of inadequate food intake, nausea, vomiting, and is described by the blend of weight pick up and

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Table 1. Emphases of the history in the evaluation of abnormal growth in children [38].

Type of History Emphases Comments Infections, placental inadequacy, poor nourishment, and adverse medication Maternal pregnancy history Medication use, infections, nutrition effects can weaken fetal development and advancement. Perinatal history may point to particu- lar pathologies, for example, hypo- Duration of gestation, perinatal informa- pituitarism or hypothyroidism; birth Perinatal and birth history tion, growth (weight and length) estimations reflect intrauterine condi- tions; duration of gestation determines pre- or post-maturity Many children have catch-up or catch-down growth between 18 and 24 months of age; growth rate percentile shifts linearly (up or down, Growth pattern in the first 3 years Establish pattern of growth depending on parents’ heights) until the child reaches his or her genetically determined growth channel or height percentile Most children with normal growth usu- ally do not cross percentiles after two Prepubertal and pubertal growth Growth pattern after 3 years of age years of age; peak height velocities velocity typically occur at Tanner stage III in girls and Tanner stage IV in boys Malnutrition is the most common cause of poor growth worldwide; thus, a detailed history of quality and quan- Nutritional history Source and quantity of nutrition tity of nutrition is critical in the evalu- ation of abnormal growth; a 24-hour food recall or three-day food diary is important in the evaluation Father’s height and age during pubertal The heights of parents determine the growth spurt; mother’s height and age heights of their children; most children Family history at menarche; heights of siblings, grand- also follow their parents’ pubertal tem- parents, uncles and aunts; medical pos; certain genetic disorders can lead conditions of family members to short or tall stature Energy level, sleep patterns, head- aches, visual changes, vomiting, A thorough systemic review evaluates abdominal pain, diarrhea, and consti- Review of systems the functional capacity of various body pation, status and progress of sexual systems maturation, medical conditions, such as polyuria, polydipsia, oliguria Psychosocial can be caused Home and school situations, stressors, Social history by severe stress from a sick home or social habits, such as tobacco use school environment

growth retardation, which leads to excessive weight-for- SHOX Mutations height [32]. Mutations in the SHOX – containing gene on the X Growth Hormone Deficiency chromosome cause a disorder in which the vital sign is short stature, which tends to be more severe in young GH deficiency usually results from the lack of GH- ladies (MIM #300582). In addition to short stature, releasing hormone. It can also be caused by a sellar and people with this mutation have a tendency to have shorter parasellar tumor that wrecks the pituitary gland itself, in lower arms and lower legs (with diminishments in arm which case there might be lacking multiple hormones traverse and leg length contrasted with trunk), Madelung delivered by the anterior pituitary. Youngsters with lack disfigurement of the lower arm (focal dysplasia of of GH can have striking growth development amid the distal radial physis), cubitus valgus, high arched development hormone substitution treatment [33].

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palate, and muscular hypertrophy as compared to those syndromes. Hypothyroidism may lead to GH deficiency; with ISS, but no SHOX mutation [34]. These skeletal this deficiency may cause micropenis, midface hypoplasia, abnormalities are like those seen in numerous patients and midline defects. Cushing syndrome can cause obesity, with Turner disorder [6]. moon facies, violaceous striae, and cessation of linear growth. Chronic renal failure can cause pallor, ashen skin Russell-Silver Syndrome discoloration, and edema. Severe hypothyroidism can increase from profound growth arrest Russell-Silver syndrome (MIM #180860, is also known with continued weight gain, sallow complexion, and as Silver-Russell syndrome and Russell-Silver dwarfism) delayed relaxation of the deep tendon reflexes. Girls with is portrayed by severe intrauterine growth limitation and classic are present with short stature, a also, postnatal growth retardation with a prominent brow, webbed neck, shield-shaped chest, and a low posterior triangular face, downturned corners of the mouth, and hairline; whereas those with mosaic Turner syndrome asymmetrical body (hemihypertrophy) [35]. may have no stigmata. Depending on the age of the child, Evaluation may cause craniotabes, bulbous wrists, and bow of the extremities [38]. The medical history plays a vital role in the assessment Laboratory Studies of short stature in the children (Table 1), including family and past therapeutic history and a complete physical A complete diagnostic evaluation should be performed examination, including phenotypic attributes, body and certain patients should be referred to a pediatric proportions and pubertal staging. Particular consideration endocrinologist (Table 2). The aim of the diagnostic should be paid to the possibility of a relationship and evaluation is to confirm or rule out specific conditions the timing of puberty in the parents and the stature of based on history and physical examination findings [39]. first- and second-degree relatives. Birth history ought This approach prevents unnecessary laboratory studies to be checked on for variations from the normal fetal because many disorders can cause short stature [38]. growth and perinatal confusions and data gathered about past sickness or indications of unending infection, Screening Tests and Initial Diagnostic Testing medicine utilization, nourishing status, and psychosocial improvement. The youngster’s and the parents’ view of When the patient’s history and physical examination the issue and also their levels of concern ought to be do not suggest a particular diagnosis, the screening surveyed. Each exertion ought to be made to acquire and laboratory tests are indicated. The tests of concern include plot all past growth estimations on the proper graph [36]. a complete blood count (CBC), erythrocyte sedimentation For the assessment of youngsters under 5 years old, rate (ESR), creatinine, electrolytes (Na, K), bicarbonate, the WHO prescribes the utilization of their recently calcium, phosphate, alkaline phosphatase, and albumin published growth curves [37]. For the evaluation of older (Table 2) [40]. children, the usage of ethnic-particular growth charts, Bone Age where accessible, is favored. For children embraced from developing countries, specific charts from the country of The assessment done in the epiphyseal ossification cause are exhorted for the first generation. Then, charts centers helps in the evaluation of bone age, which particular to the embracing nation appear to be more provides an estimate of a child’s skeletal maturation [40]. fitting [21]. The assessment of bone age assists in the determination Physical and Dental Examination of the child’s growth potential depending on established norms. The skeletal maturity pattern plays a vital role in the differentiation of different types of short stature. Abnormal growth patterns can be differentiated from In patients with a constitutional delay of growth and normal variants by thorough physical examination, and puberty (CDGP), bone age corresponds with height & it also identifies specific dysmorphic features of genetic

Table 2. General screening tests in the evaluation of abnormal growth in children [38].

Test Function CBC with differential Evaluates for anemia, blood dyscrasia, and infections Rules of renal disease and electrolyte abnormalities that Basic metabolic panel could occur with Bartter syndrome, other renal or metabolic disorders, and diabetes insipidus Assesses metabolic or infectious disorders associated with Liver function testing liver dysfunction Urinalysis and urine pH level Assesses kidney function and rules of renal tubular acidosis ESR Evaluates for chronic inflammatory states

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age and is typically delayed by 2 SD; and in patients with Conflict of Interests short pathologic stature, bone age is severely hampered None (usually more than 2 SD), and the delay worsens over time [40]. Ethical Approval Not required Genetic Tests Consent for Publication When the diagnosis determines that the cause of the short Not applicable stature disease is due to genetic, the genes of interest Author details should be examined. The assessment of SHOX gene is Rawan Ali Almutairi1 not necessary to be undertaken in all children with ISS, 1. King Khalid University Hospital, King Saud University, but it should be in mind for any patient with clinical Riyadh, Saudi Arabia findings compatible with SHOX haploinsufficiency [39]. References Treatment 1. Cakan N, Kamat D. Short stature in children: a practical We can classify the short stature children regarding the approach for primary care providers. Clin Pediatr 2007; treatment into two categories; the children with short 46(5):379–85. stature that is related to GH deficiency, and the children 2. Pedicelli S, Peschiaroli E, Violi E, Cianfarani S. Controversies with short stature that is not related to GH deficiency [41]. in the definition and treatment of idiopathic short stature (ISS). J Clin Res Inpediatr Endocrinol 2009; 1(3):105–15. Non-GH deficiency short stature can be managed by 3. August GP. Growth and development in the normal infant receiving different recommendations options that vary in and child. In: Principles and Practice of Endocrinology and complexity and costs and for which the relative benefits Metabolism. 1990, pp. 72–80. and risks are not determined. Treatment strategy often depends on the decision that is taken by the primary care 4. El-Mouzan MI, Al-Herbish AS, Al-Salloum AA, Foster PJ, physician about whether to refer the child to a specialist Al-Omar AA, Qurachi MM, et al. Regional disparity in prevalence of malnutrition in Saudi children. Saudi Med to rule out a pathologic cause of short stature [34].The J 2010; 31(5):550–4. rationale for treating short stature in childhood includes increasing height and alleviating psychosocial disability 5. Bender MK. Centers for disease control and prevention while maintaining favorable risk: benefit and cost: benefit growth charts versus breastfeeding? Pediatrics 2002; 110(3):648. ratios [42]. 6. Rogol AD. Causes of short stature. UpToDate online Conclusion [Internet]. 2008. Available via https://www.uptodate. com/contents/causes-of-short-stature (Accessed The prevalence of short stature in children is slightly November 2017). higher in males than in females. There is a wide range 7. Richmond EJ, Rogol AD. Diagnosis of growth hormone of reasons that may cause shortness of stature in children deficiency in children. In: Rose BD, editor. Up-to-date including; familial (genetic) short stature, CDGP, [Internet]. 2008. Available via http://www.uptodate. which are normal variants of growth, cardiac diseases, com/contents/diagnosis-of-growth-hormone-deficiency- gastrointestinal diseases, immunologic diseases, in-children (Accessed November 2017). pulmonary diseases, genetic disorders, and cancer. 8. Cuttler L, Silvers JB. Growth hormone and health policy. J Knowledge of the patient history is the most important Clin Endocrinol Metabol 2010; 95(7):3149–53. step in the diagnosis of children with short stature. The 9. El Mouzan MI, Al Herbish AS, Al Salloum AA, Foster PJ, short stature in children can be classified regarding the Al Omer AA, Qurachi MM. Prevalence of short stature treatment into two categories; the children with short in Saudi children and adolescents. Ann Saudi Med 2011; stature that is related to GH deficiency and the children 31(5):498–501. http://doi:10.4103/0256-4947.84628 with short stature that is not related to GH deficiency. 10. Mikki N, Abdul-Rahim HF, Awartani F, Holmboe-Ottesen G. Prevalence and sociodemographic correlates of stunting, Acknowledgements underweight, and overweight among Palestinian school None adolescents (13–15 years) in two major governorates in List of abbreviations the West Bank. BMC Public Health 2009; 9(1):485. CBC Complete blood count 11. Haboubi GJ, Shaikh RB. A comparison of the nutritional CDGP Constitutional delay of growth and puberty status of adolescents from selected schools of South India ESR Erythrocyte sedimentation rate and UAE: a cross-sectional study. Indian J Community Med ISS Idiopathic short stature 2009; 34(2):108–11. JIA Juvenile idiopathic arthritis 12. Wang Y, Popkin B, Zhai F. The nutritional status and dietary pattern of Chinese adolescents, 1991 and 1993. Funding Eur J Clin Nutr 1998; 52(12):908–16. None 13. Kimani-Murage EW, Kahn K, Pettifor JM, Tollman SM, Dunger DB, Gómez-Olivé XF, et al. The prevalence of

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